DESCRIPTION: HIV-infected (HIV+) and elderly individuals are the main adult populations for whom pneumococcal vaccine is recommended as they are highly susceptible to Streptococcus pneumoniae (pneumococcus), the leading cause of community acquired and in-hospital pneumonia in the U.S. and globally. In late fall 2012, a 13 valent pneumococcal capsular polysaccharide (PPS) conjugate vaccine (PCV13) recommended for infants/children since 2010 and approved for adults since 2011, was recommended for HIV+ adults. The goal of this project, submitted in response to PAR 12-175 Multidisciplinary studies of HIV/AIDS and Aging, is to determine the effects of aging and HIV infection PCV13 response. In prior work, our group discovered links between B cell and antibody repertoire deficiencies and impaired PPS antibody responses in HIV+ individuals and identified novel functional activities of PPS antibodies that protect against pneumococcal sepsis and pneumonia in mice. Informed by these studies, we will perform in depth analyses of the serological, B cell, functional and molecular responses to PCV13 of middle aged (50-65 yrs) and elderly (>65 yrs) HIV+ and HIV- individuals and assemble the data into serological and molecular signatures of PCV13 response. We will use standard serological and functional assays along with novel assays of PPS antibody functional activity against clinically important pneumococcal serotypes that PCV13 was developed to prevent. Then, we will use systems biology to identify molecular mechanisms of PCV13 response and assemble B cell, serological and transcriptional profiles into biomarkers of response. The specific aims of this project are: 1) To determine the effects of age and HIV infection on the antibody and B cell response to PCV13; 2) To determine the effects of age and HIV infection on PCV13-elicited antibody functional activity; 3) To determine the effects of age and HIV infection on the molecular response to PCV13. As biomarkers of adult pneumococcal vaccine response are not available, those identified in this study will fill a major gap and provid a platform to decipher PCV13 efficacy, a roadmap to guide future vaccine use in elderly HIV+ and HIV- individuals, clues to improve vaccine immunogenicity, and pathways to develop new approaches to prevent pneumococcal disease in those who are most at risk.